Biology subjects

Martin-Gutierrez, L.

Publications and source records attributed to Martin-Gutierrez, L..

3 recordsLinked to original sources

bioRxiv2024

Oestrogen influences B cell class-switching in individuals with an XX sex chromosome complement

Sex differences in humoral immunity are well-documented, though the mechanisms underpinning these differences remain ill-defined. Here, we demonstrate that post-pubertal cisgender females have higher levels of class-switched B cells compared to age-matched cisgender males. However, whilst sex chromosome-encoded genes characterise most of the differences in total B cell transcriptomes between cisgender-females and -males, sex differences in class-switched B cells are only observed post-pubertally. Accordingly, B cells express high levels of oestrogen receptor 2 (ESR2) and genes known to regulate B cell class-switching are enriched for ESR2-binding sites. Using a gender-diverse cohort of young people, we show that in transgender males (XX chromosomal background), blockade of natal oestrogen reduced the frequency of class-switched B cells, whilst gender-affirming oestradiol treatment in transgender females (XY chromosomal background), did not increase the frequency of class-switched B cells. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with oestrogen only supporting B cell class-switching on an XX chromosomal background. eTOC summarySex hormones and chromosomes work in tandem to impact immune responses, with oestrogen influencing B cell class-switching exclusively on an XX chromosomal background.

immunology↗

bioRxiv2019

Activation of the liver X receptors alters CD4+ T cell membrane lipids and signalling through direct regulation of glycosphingolipid synthesis

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells, and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol) which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase (UGCG) as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened pro-inflammatory T cell function. Finally, compared to responder T cells, regulatory T cells had a distinct pattern of LXR-target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a novel mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism, and demonstrate its relevance in modulating T cell function.

immunology↗

bioRxiv2017

Changes In LXRα Phosphorylation Promote A Novel Diet-Induced Transcriptome That Alters The Transition From Fatty Liver To Steatohepatitis

Understanding the transition from fatty liver or steatosis to more advanced inflammatory and fibrotic stages of non-alcoholic fatty liver disease (steatohepatitis), is key to define strategies that alter or even reverse the progression of this pathology. The Liver X Receptor alpha (LXR) controls hepatic lipid homeostasis and inflammation. Here we show that mice carrying a mutation that abolishes phosphorylation at Ser196 (S196A) in LXR exhibit reduced hepatic inflammation and fibrosis when challenged with a high fat-high cholesterol diet, despite displaying enhanced hepatic lipid accumulation. This protective effect is associated with reduced cholesterol accumulation, a key promoter of lipid-mediated hepatic damage. Reduced steatohepatitis in S196A mice involves the reprogramming of the liver transcriptome by promoting diet-induced changes in the expression of genes involved in endoplasmic reticulum stress, extracellular matrix remodelling, inflammation and lipid metabolism. Unexpectedly, changes in LXR phosphorylation uncover novel diet-specific target genes, whose regulation does not simply mirror ligand-induced LXR activation. These unique LXR phosphorylation-sensitive, diet-responsive target genes are revealed by promoting LXR occupancy and cofactor recruitment in the context of a cholesterol-rich diet. Therefore, LXR phosphorylation at Ser196 critically acts as a novel nutritional sensor that promotes a unique diet-induced transcriptome thereby modulating metabolic, inflammatory and fibrotic responses important in the transition to steatohepatitis.

pathology↗